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  • Adenosine A1 receptor stimulation reduces D1 receptor-mediated GABAergic transmission from striato-nigral terminals and attenuates l-DOPA-induced dyskinesia in dopamine-denervated mice.

Adenosine A1 receptor stimulation reduces D1 receptor-mediated GABAergic transmission from striato-nigral terminals and attenuates l-DOPA-induced dyskinesia in dopamine-denervated mice.

Experimental neurology (2014-09-01)
Dalila Mango, Alessandra Bonito-Oliva, Ada Ledonne, Loredana Cappellacci, Riccardo Petrelli, Robert Nisticò, Nicola Berretta, Gilberto Fisone, Nicola Biagio Mercuri
ABSTRACT

γ-Aminobutyric acid A receptor (GABAAR)-mediated postsynaptic currents were recorded in brain slices from substantia nigra pars reticulate neurons. The selective adenosine A1 receptor (A1R) antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), increased the frequency, but not the amplitude of spontaneous inhibitory post-synaptic currents (IPSCs) in the presence of the dopamine D1 receptor agonist SKF 38393 (SKF) and phosphodiesterase 10A inhibitors (papaverine or AE90074). Under these conditions, DPCPX also increased the amplitude of evoked IPSCs (eIPSCs). The effect of DPCPX was also examined in a mouse model of Parkinson's disease (PD), generated by unilateral denervation of the dopaminergic input to the striatum. In this model, SKF alone was sufficient to increase sIPSCs frequency and eIPSCs amplitude, and these effects were not potentiated by DPCPX. To confirm a depressive effect of A1Rs on the synaptic release of GABA we used the selective A1R agonist 5'-chloro-5'-deoxy-N(6)-(±)-(endo-norborn-2-yl)adenosine (5'Cl5'd-(±)-ENBA) which has limited peripheral actions. We found that 5'Cl5'd-(±)-ENBA decreased sIPSCs frequency, without affecting their amplitude, and decreased eIPSCs amplitude. Importantly, in the PD mouse model, 5'Cl5'd-(±)-ENBA prevented the increase in sIPSC frequency and eIPSC amplitude produced by SKF. Since exaggerated DA transmission along the striato-nigral pathway is involved in the motor complications (e.g. dyskinesia) caused by prolonged and intermittent administration of l-DOPA, we examined the effect of A1R activation in mice with unilateral DA denervation. We found that 5'Cl5'd-(±)-ENBA, administered in combination with l-DOPA, reduced the development of abnormal involuntary movements. These results indicate the potential benefit of A1R agonists for the treatment of l-DOPA-induced dyskinesia and hyperkinetic disorders providing a mechanistic framework for the study of the interaction between DA and adenosine in the striatonigral system.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
8-Cyclopentyl-1,3-dipropylxanthine, solid
Sigma-Aldrich
CNQX, ≥98% (HPLC), solid
USP
Levodopa, United States Pharmacopeia (USP) Reference Standard
Supelco
Levodopa, Pharmaceutical Secondary Standard; Certified Reference Material
Levodopa, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Hydrogen bromide, ReagentPlus®, ≥99%
Sigma-Aldrich
6-Hydroxydopamine hydrochloride, ≥97% (titration), powder
Sigma-Aldrich
Benserazide hydrochloride, ≥98% (HPLC), solid
Sigma-Aldrich
3,4-Dihydroxy-L-phenylalanine, ≥98% (TLC)
Sigma-Aldrich
Hydrobromic acid, reagent grade, 48%
Sigma-Aldrich
Hydrobromic acid solution, 33 wt. % in acetic acid
Benserazide hydrochloride, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Hydrogen bromide solution, 33 wt. % in acetic acid
Sigma-Aldrich
Hydrobromic acid, 48 wt. % in H2O, ≥99.99%
Sigma-Aldrich
Hydrobromic acid, ACS reagent, 48%